Perturbateurs endocriniens et troubles du comportement

Prenatal environmental events that disturb neurodevelopment are suspected to increase the risk of psychiatric disorders. Estrogenic hormones such as diethylstilbestrol (DES) and environmental monomers like Bisphenol A (BPA) have the potential to disturb the development of the foetus and especially its brain. We reviewed the epidemiological studies investigating a possible association between prenatal DES or BPA exposure and risk of psychiatric disorders and discussed the hypothetical biological mechanisms linking this prenatal exposure with psychiatric disorders. The principal methodological issues that could represent confounding factors and may explain conflicting results are discussed. Interestingly, prenatal exposure to DES and BPA has been linked to epigenetic alterations associated with urogenital lesions observed in the exposed offspring, supporting the hypothesis that this environmental factor can indeed alter epigenetic regulations. Following the same line of thinking, these endocrine disruptors may modify the epigenetic mechanisms involved in neurodevelopment and, in turn, increase the occurrence of psychiatric disorders.     

Prenatal Exposure to TCDD Triggers Significant Modulation of microRNA Expression Profile in the Thymus That Affects Consequent Gene Expression

Background

MicroRNAs (miRs) are a class of small RNAs that regulate gene expression. There are over 700 miRs encoded in the mouse genome and modulate most of the cellular pathways and functions by controlling gene expression. However, there is not much known about the pathophysiological role of miRs. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), an environmental contaminant is well known to induce severe toxicity (acute and chronic) with long-term effects. Also, in utero exposure of fetus to TCDD has been shown to cause thymic atrophy and alterations in T cell differentiation. It is also relevant to understand “the fetal basis of adult disease” hypothesis, which proposes that prenatal exposure to certain forms of nutritional and environmental stress can cause increased susceptibility to clinical disorders later in life. In the current study, therefore, we investigated the effects of prenatal exposure to TCDD on miR profile in fetal thymocytes and searched for their possible role in causing thymic atrophy and alterations in the expression of apoptotic genes.

Methodology/Principal Findings

miR arrays of fetal thymocytes post exposure to TCDD and vehicle were performed. Of the 608 mouse miRs screened, 78 miRs were altered more than 1.5 fold and 28 miRs were changed more than 2 fold in fetal thymocytes post-TCDD exposure when compared to vehicle controls. We validated the expression of several of the miRs using RT-PCR. Furthermore, several of the miRs that were downregulated contained highly complementary sequence to the 3′-UTR region of AhR, CYP1A1, Fas and FasL. Also, the Ingenuity Pathway Analysis software and database was used to analyze the 78 miRs that exhibited significant expression changes and revealed that as many as 15 pathways may be affected.

Conclusions/Significance

These studies revealed that TCDD-mediated alterations in miR expression may be involved in the regulation of its toxicity including cancer, hepatic injury, apoptosis, and cellular development.     

Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

Prenatal Adversity Modulates the Quality of Maternal Care Via the Exposed Offspring

Adversities in pregnancy, including poor diet and stress, are associated with increased risk of developing both metabolic and mental health disorders later in life, a phenomenon described as fetal programming or developmental origins of disease. Predominant hypotheses proposed to explain this relationship suggest that the adversity imposes direct changes to the developing fetus which are maintained after birth resulting in an increased susceptibility to ill health. However, during pregnancy the mother, the developing fetus, and the placenta are all exposed to the adversity. The same adversities linked to altered offspring outcome can also result in suboptimal maternal care, which is considered an independent adverse exposure for the offspring. Recent key experiments in mice reveal the potential of prenatal adversity to drive alterations in maternal care through abnormal maternal–pup interactions and via alterations in placental signaling. Together, these data highlight the critical importance of viewing fetal programming holistically paying attention to the intimate, bidirectional, and reiterative relationship between mothers and their offspring.     

Advances in research into gamete and embryo-fetal origins of adult diseases

The fetal and infant origins of adult disease hypothesis proposed that the roots of adult chronic disease lie in the effects of adverse environments in fetal life and early infancy. In addition to the fetal period, fertilization and early embryonic stages, the critical time windows of epigenetic reprogramming, rapid cell differentiation and organogenesis, are the most sensitive stages to environmental disturbances. Compared with embryo and fetal development, gametogenesis and maturation take decades and are more vulnerable to potential damage for a longer exposure period. Therefore, we should shift the focus of adult disease occurrence and pathogenesis further back to gametogenesis and embryonic development events, which may result in intergenerational, even transgenerational, epigenetic re-programming with transmission of adverse traits and characteristics to offspring. Here, we focus on the research progress relating to diseases that originated from events in the gametes and early embryos and the potential epigenetic mechanisms involved.     

Convergence and Divergence in the Etiology of Myelin Impairment in Psychiatric Disorders and Drug Addiction

Impairment of oligodendroglia (OL)-dependent myelination in the central nervous system (CNS) is a remarkable parallel recently identified in major psychiatric disorders and chronic drug abuse. Neuroimaging and neuropathological studies revealed myelin defects and microarray-profiling analysis demonstrated aberrant expression of myelin-related genes in schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD) and cocaine addiction. However, the etiology underlying myelin impairment in these clinically distinct subjects remains elusive. This article reviews myelin impairment in line with dopaminergic dysfunction, a prime neuropathophysiological trait shared in psychiatric disorders and drug abuse, as well as the genetic and epigenetic alterations associated with these diseases. The current findings support the hypothesis that aberrant dopamine (DA) action on OLs is a common pathologic mechanism for myelin impairment in the aforementioned mental morbidities, whereas inherited genetic variations that specifically affect OL development and myelinogenesis may further increase myelin vulnerability in psychiatric disorders. Importantly, OL defect is not only a pathological consequence but also a causative factor for dopaminergic dysfunction. Hence, myelin impairment is a key factor in the pathogenic loop of psychiatric diseases and drug addiction. Special issue article in honor of Dr. Ji-Sheng Han.     

A genomic point-of-view on environmental factors influencing the human brain methylome

The etiologic paradigm of complex human disorders such as autism is that genetic and environmental risk factors are independent and additive, but the interactive effects at the epigenetic interface are largely ignored. Genomic technologies have radically changed perspective on the human genome and how the epigenetic interface may impact complex human disorders. Here, I review recent genomic, environmental, and epigenetic findings that suggest a new paradigm of “integrative genomics” in which genetic variation in genomic size may be impacted by dietary and environmental factors that influence the genomic saturation of DNA methylation. Human genomes are highly repetitive, but the interface of large-scale genomic differences with environmental factors that alter the DNA methylome such as dietary folate is under-explored. In addition to obvious direct effects of some environmental toxins on the genome by causing chromosomal breaks, non-mutagenic toxin exposures correlate with DNA hypomethylation that can lead to rearrangements between repeats or increased retrotransposition. Since human neurodevelopment appears to be particularly sensitive to alterations in epigenetic pathways, a further focus will be on how developing neurons may be particularly impacted by even subtle alterations to DNA methylation and proposing new directions towards understanding the quixotic etiology of autism by integrative genomic approaches.     

Prenatal programing: At the intersection of maternal stress and immune activation

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Exposure to prenatal insults such as maternal stress and pathogenic infections has been associated with an increased risk for neurodevelopmental disorders. The mechanisms by which these programing events occur likely involve complex interactions between the maternal hormonal milieu, the placenta, and the developing fetus, in addition to compounding factors such as fetal sex and gestational stage of development. Despite the diverse biological processes involved, examination of common pathways in maternal stress and immune activation offers intriguing possibilities for elucidation of mechanistic insight. Further, the endocrine and sex-specific placenta is a tissue poised to be a key mediator in fetal programing, located at the intersection of the maternal and embryonic environments. In this review, we will discuss the potential shared mechanisms of maternal stress and immune pathway activation, with a particular focus on the important contribution and role of the placenta. This article is part of a Special Issue entitled (The Neuroendocrine-Immune).     

The effect of environmental harshness on neurogenesis: a large-scale comparison

Harsh environmental conditions may produce strong selection pressure on traits, such as memory, that may enhance fitness. Enhanced memory may be crucial for survival in animals that use memory to find food and, thus, particularly important in environments where food sources may be unpredictable. For example, animals that cache and later retrieve their food may exhibit enhanced spatial memory in harsh environments compared with those in mild environments. One way that selection may enhance memory is via the hippocampus, a brain region involved in spatial memory. In a previous study, we established a positive relationship between environmental severity and hippocampal morphology in food-caching black-capped chickadees (Poecile atricapillus). Here, we expanded upon this previous work to investigate the relationship between environmental harshness and neurogenesis, a process that may support hippocampal cytoarchitecture. We report a significant and positive relationship between the degree of environmental harshness across several populations over a large geographic area and (1) the total number of immature hippocampal neurons, (2) the number of immature neurons relative to the hippocampal volume, and (3) the number of immature neurons relative to the total number of hippocampal neurons. Our results suggest that hippocampal neurogenesis may play an important role in environments where increased reliance on memory for cache recovery is critical.     

Fetal tissue sampling--indications,techniques, complications,and experience with sampling of fetal skin,liver, and muscle.

Invasive prenatal testing has become an important way to evaluate fetuses at increased risk for hereditary disorders. In utero sampling of fetal skin, liver, and muscle may be required to diagnose before-birth disorders that cannot be diagnosed by analysis using chorionic villi or amniotic fluid. In the next few years, many of these conditions will be detected by DNA analysis, and the need for these procedures may decrease dramatically. First performed by fetoscopy, fetal tissue sampling is now most frequently done by inserting a biopsy needle under continuous ultrasonographic guidance. We describe the indications, techniques, complications, and experience with obtaining fetal skin, liver, and muscle biopsy specimens.     

A genomic point-of-view on environmental factors influencing the human brain methylome

The etiologic paradigm of complex human disorders such as autism is that genetic and environmental risk factors are independent and additive, but the interactive effects at the epigenetic interface are largely ignored. Genomic technologies have radically changed perspective on the human genome and how the epigenetic interface may impact complex human disorders. Here, I review recent genomic, environmental and epigenetic findings that suggest a new paradigm of “integrative genomics” in which genetic variation in genomic size may be impacted by dietary and environmental factors that influence the genomic saturation of DNA methylation. Human genomes are highly repetitive, but the interface of large-scale genomic differences with environmental factors that alter the DNA methylome such as dietary folate is under-explored. In addition to obvious direct effects of some environmental toxins on the genome by causing chromosomal breaks, non-mutagenic toxin exposures correlate with DNA hypomethylation that can lead to rearrangements between repeats or increased retrotransposition. Since human neurodevelopment appears to be particularly sensitive to alterations in epigenetic pathways, a further focus will be on how developing neurons may be particularly impacted by even subtle alterations to DNA methylation and proposing new directions towards understanding the quixotic etiology of autism by integrative genomic approaches.Key words: DNA methylation, copy number variation, autism, neurodevelopment, genomics, epigenomics, epigenetics, folate, folic acid, environmental exposures, Alu, MeCP2, LINE-1     

Prenatal Stress Impairs Spinal Cord Oligodendrocyte Maturation via BDNF Signaling in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring’s brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis.

     

Bacteriohopanepolyols across environmental gradients in Lake Vanda,Antarctica

Bacteriohopanepolyols (BHPs) are bacterial membrane lipids that may be used as biological or environmental biomarkers. Previous studies have described the diversity, distribution, and abundance of BHPs in a variety of modern environments. However, the regulation of BHP production in polar settings is not well understood. Benthic microbial mats from ice‐covered lakes of the McMurdo Dry Valleys, Antarctica provide an opportunity to investigate the sources, physiological roles, and preservation of BHPs in high‐latitude environments. Lake Vanda is one of the most stable lakes on Earth, with microbial communities occupying specific niches along environmental gradients. We describe the influence of mat morphology and local environmental conditions on the diversity and distribution of BHPs and their biological sources in benthic microbial mats from Lake Vanda. The abundance and diversity of C‐2 methylated hopanoids (2‐MeBHP) are of particular interest, given that their stable degradation products, 2‐methylhopanes, are among the oldest and most prevalent taxonomically informative biomarkers preserved in sedimentary rocks. Furthermore, the interpretation of sedimentary 2‐methylhopanes is of great interest to the geobiology community. We identify cyanobacteria as the sole source of 2‐MeBHP in benthic microbial mats from Lake Vanda and assess the hypothesis that 2‐MeBHP are regulated in response to a particular environmental variable, namely solar irradiance.     

Urban birds have broader environmental tolerance

Urbanization dramatically changes the composition and diversity of biotic communities. The characteristics distinguishing species that persist in urban environments, however, are poorly understood. Here we test the hypothesis that broadly adapted organisms are better able to tolerate urbanization, using a phylogenetically controlled, global comparison of birds. We compared elevational and latitudinal distributions of 217 urban birds found in 73 of the world's largest cities with distributions of 247 rural congeners to test the hypothesis that urban birds possess broader environmental tolerance. Urban birds had markedly broader environmental tolerance than rural congeners, as estimated by elevational and latitudinal distributions. Our results suggest that broad environmental tolerance may predispose some birds to thrive in urban habitats. The mechanisms mediating such environmental tolerance warrant further investigation, but probably include greater behavioural, physiological and ecological flexibility.     

Laboratory assessment of temperament and environmental enrichment in rhesus monkey infants (Macaca mulatta)

This study investigated the combined effects of early temperamental characteristics and environmental enrichment on a variety of developmental measures in nursery-reared rhesus monkey infants. Twenty-three infants, reared in either standard laboratory cages or enriched environments, were tested during the 1st month of life for interactive, motor, and temperamental capabilities and characteristics. At 8 months of age, all subjects were assessed on a second series of tests designed to measure their problem-solving skills, motor capabilities, and temperamental responses under challenge. Results indicated that enrichment was associated with higher scores on subsequent problem-solving and motor tests. However, such effects were found to combine with early temperament ratings. Specifically, individuals performing best on the 8-month tests had not only been reared in enriched environments, but also had been rated low on fearfulness during the early assessment. In addition, individuals scoring poorest had been rated as fearful initially in addition to being reared without enrichment. Results indicated that while high ratings on early laboratory assessments of fearfulness may be predictive of poorer problem-solving performance under challenging conditions, these adverse effects may be partially attenuated by environmental enrichment.     

Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities

Background

Women are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI.

Methodology/Principal Findings

In order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring.

Conclusions

These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.     

Role of sound stimulation in reprogramming brain connectivity

Sensory stimulation has a critical role to play in the development of an individual. Environmental factors tend to modify the inputs received by the sensory pathway. The developing brain is most vulnerable to these alterations and interacts with the environment to modify its neural circuitry. In addition to other sensory stimuli, auditory stimulation can also act as external stimuli to provide enrichment during the perinatal period. There is evidence that suggests that enriched environment in the form of auditory stimulation can play a substantial role in modulating plasticity during the prenatal period. This review focuses on the emerging role of prenatal auditory stimulation in the development of higher brain functions such as learning and memory in birds and mammals. The molecular mechanisms of various changes in the hippocampus following sound stimulation to effect neurogenesis, learning and memory are described. Sound stimulation can also modify neural connectivity in the early postnatal life to enhance higher cognitive function or even repair the secondary damages in various neurological and psychiatric disorders. Thus, it becomes imperative to examine in detail the possible ameliorating effects of prenatal sound stimulation in existing animal models of various psychiatric disorders, such as autism.